Nicole L. Mihalopoulos, MD, MPH is an Assistant Professor in the Department of Pediatrics at the University of Utah. The purpose of this Mentored Patient-Oriented Career Development Award is to provide Dr. Mihalopoulos with a structured Career Development Program and a mentored research plan that will enable her to become an independent clinical researcher in the field of preventive cardiology. Dr. Mihalopoulos' specific interest is in the field of adolescent obesity and adipokines, specifically how differing levels of adipokines may protect some obese individuals from developing metabolic dysfunction. This K23 award investigates why some obese children, adolescents and adults exhibit evidence of metabolic dysfunction (dyslipidemia, insulin resistance, hypertension) and some do not. Specifically, she will study how adiponectin and leptin, two adipokines that affect insulin resistance and lipid metabolism, and brown adipose tissue (BAT) activity influence this variation. She will expand her knowledge and skill in this area with the following specific aims. Specific Aim 1 will evaluate the relationship between BAT, the adiponectin/leptin (A/L) ratio, and metabolic dysfunction in children, adolescents, and adults. This aim includes two crosssectional studies. In study 1A, BAT activity, A/L ratios and metabolic measures will be determined in 600 subjects (8-99yo) who are undergoing a clinically indicated positron emission tomography with computed tomography (PET/CT). In study 1B similar measures, including a PET/CT, will be performed on 60 obese, but otherwise healthy, older adolescents/young adults (18-30yo) recruited from Dr. Mihalopoulos' Adolescent Preventive Cardiology Clinic and Dr. Steven C. Hunt's cardiovascular genetics extremely obese cohorts. These two studies will evaluate possible correlations between BAT activity, A/L ratio and metabolic dysfunction. Specific Aim 2 will determine whether serum concentrations of adiponectin and leptin are associated with metabolic dysfunction during puberty among obese and normal weight children and adolescents. This aim includes two longitudinal studies. Study 2A is a longitudinal cohort of 642 primarily normal weight black and white children and adolescents from Project HeartBeat! (PHB) established by Dr. Darwin R. Labarthe. PHB was unique because it followed children every 4 months for four years (1991-1995) to assess changes in lipids and anthropometry during puberty. In study 2B, 220 obese children and adolescents (8-18yo) recruited from Dr. Mihalopoulos' Adolescent Preventive Cardiology Clinic and Dr. Steven C. Hunt's cardiovascular genetics extremely obese cohorts will have annual determinations of adiponectin and leptin for as long as 4 years. Study 2B will provide data describing how the A/L ratio changes during puberty in obese children and adolescents. This proposal takes advantage of expertise in pediatric cardiology, intermediary metabolism of adipose tissue, positron emission tomography, cardiovascular disease genetics, pediatric endocrinology, genetic epidemiology and multi-level statistical modeling found within the University of Utah. Dr. Mihalopoulos has also identified experts in brown adipose tissue metabolism and preventive cardiology to serve as advisors. Completion of the four studies will provide a much better understanding of whether variations in BAT and the A/L ratio are responsible for variations in cardiovascular disease risk among the obese. Determining the factors that appear to provide protection for some obese youth and adults from developing metabolic dysfunction will enable Dr. Mihalopoulos to pursue future studies of strategies to reduce the risk of cardiovascular disease risk. At the completion of the training program, Dr. Mihalopoulos will be poised to be an independent investigator in the field of preventive cardiology with experience in study design, laboratory skills, positron emission tomography and statistical techniques. PUBLIC HEALTH RELEVANCE: This proposal has both clinical and public health significance because little is known about the metabolic function and significance of adipose tissue during puberty. This study will increase our understanding of the role of adipose tissue before, during, and after puberty and may lead to early identification of risk factors and intervention to prevent cardiovascular disease.